The present invention provides a novel compound, novel compositions, methods of their use and methods of their manufacture, such compound being pharmacologically useful in inducing diuresis in a mammal and in the treatment of hypertension in a mammal. More specifically, the compound of the present invention is an orally active diol metabolite of a 7-phenyl-1 1,2,4-triazolo[2,3-c]pyrimidine-5-amine, which has diuretic activity comparable to that of its precursor, but with a lower incidence of side effects, especially cardiotoxic side effects.
Diuretics are drugs used to increase the volume of urine excreted by the kidneys. They are employed principally for the relief of edema and ascites. They are also especially useful in the treatment of hypertension. These conditions occur in diseases of the heart, kidneys and liver. Diuretics are most effective in the treatment of cardiac edema, particularly that associated with congestive heart failure. They are also used in the ascites of cirrhosis, nephrotic syndrome, diabetes insipidus, hypertension, edema of pregnancy, and to reduce cerebrospinal and intraocular fluid pressure. Some diuretics have highly specialized uses in glaucoma, hyperkalemia, bromide intoxication, anginal syndrome, epilepsy, migraines, and in premenstrual syndrome (i.e. conditions in which edema is not present or at least not definitely established).
The formation of urine from the blood, in simplest terms, consists of glomerular filtration and selective tubular reabsorption and secretion. As the glomerular filtrate passes through the tubules, substances essential to the blood and tissues - water, glucose, salts and amino acids - are reabsorbed. Other substances in the glomerular filtrate, such as urea, are not as readily absorbed by the tubules. Thus, it is thought that in the renal tubule, there is a specific mechanism for the transport of each ionic species, the capacities of which are guite different. For example, the capacity of the renal tubule to reabsorb sulfate ion is limited. By contrast, the tubular capacity for the reabsorption of phosphate is such that sufficient phosphate is reabsorbed to maintain the normal extracellular level and an excess is excreted. On the other hand, much larger amounts of bicarbonate ion and chloride ion can be reabsorbed.
Thiazide diuretics act mainly to block sodium and chloride reabsorption a the first (thick) portion of the distal tubule. They also have a mild anti-carbonic anhydrase effect. The resultant natriuresis is accompanied by increased excretion of potassium, bicarbonate, chloride and water.
The antihypertensive action of the thiazides is attributable to two factors: (a) depletion of sodium and subsequent reduction in plasma volume and (b) a decrease in peripheral resistance. The latter is thought t be due to the loss of sodium from the arteriolar wall or a direct action on the vascular bed. In addition, there is some inhibition of the pressor activity of norepinephrine. On the other hand, quantitative hypersensitivity to diuretics is frequently encountered. Other possible drawbacks are potassium deficiency, magnesium deficiency, pancreatitis, decreased glucose tolerance, increased uric acid levels and increased anticoagulant effects.
The compound of the general formula I: ##STR1## is disclosed in U.S. Pat. No. 4,405,780. This compound is a triazolopyrimidine diuretic which increases glomerular filtration rate and renal blood flow acutely in mammals. Chronic oral dosing showed significant increases in renal blood flow, glomerular filtration rate and sodium excretion.
The compound of the general formula II: ##STR2## is disclosed in U.S. Pat. No. 4,483,987. Compound II is the o dealkylated metabolite of Compound I. It was subsequently discovered in this invention that compound II undergoes aliphatic hydroxylation in the rat. This was surprising and unexpected, since similar metabolism is not seen in man. The product of the subsequent hydroxylation step is represented by structural formula III: ##STR3## The compound of III provided three distinct surprising and unexpected advantages over either of the precursor compounds. Compound III is more water soluble, is more bioavailable, and shows no incidence of cardiotoxic side effects in rats.